Complex neural circuits and a large number of peptide hormones and neuropeptides control feeding and energy expenditure. The VGF (non-acronymic) gene encodes a highly conserved mammalian polypeptide that is differentially cleaved in a tissue-specific manner and secreted from endocrine, neuroendocrine and neuronal cells. We have shown that targeted deletion of VGF results in profound alterations in the regulation of feeding and energy balance; VGF mutant mice are lean, hyperactive, hypermetabolic and highly resistant to obesity and diabetes. Interestingly, a number of independent genetic linkage studies have consistently shown strong evidence of a subregion linked with obesity over the VGF locus on 7q22.1 but the causative gene has not been identified. Based on its consistent linkage in independent studies and strong biological candidacy, we hypothesize that VGF is an excellent candidate gene for human obesity and leanness, and propose to investigate this using combined clinical and basic science approaches. One of us (JAM) will perform genetic association studies using a high density panel of single nucleotide polymorphisms (SNPs) in the Quebec Family Study (QFS) patient cohort who represents well-characterized samples from 950 individuals and 223 families. Several nonsynonymous, protein-altering SNPs are already known and additional SNPs across the VGF locus will be developed and fully characterized as potential functional variants and/or biomarkers. These SNPs and haplotype blocks will then be validated in a second, independent cohort of 1,425 individuals. Concurrent biologic studies (SRJS) will investigate the function of select human VGF SNPs in mouse models using gene 'knockout' and 'knock-in' strategies, and in various in vitro cell culture models where VGF expression, processing, and regulated release can be quantified. Since targeted VGF deletion generates mice that are lean and resistant to diet-induced and some forms of genetically-induced obesity, tissues from these mice, including adipose and muscle, will be used to identify additional gene products by high-density gene expression array analysis. These physiologically linked, target-tissue genes may themselves play a functional role in obesity resistance or susceptibility, and thus become excellent candidates for future investigation.